PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is characterized by a severe narrowing of pre-capillary pulmonary arteries due to a combination of increased muscularization and formation of plexiform lesions. PAH has a high mortality rate (15% 1-year mortality) resulting in ~15,000 deaths annually in the United States alone. Mutations in BMPR2 have been identified in >70% of patients with hereditary PAH and also some cases of sporadic PAH; however, no new and fully effective treatments have been developed based on these findings. In the proposed studies, we will focus on understanding the underlying molecular disease mechanisms using a mouse model that expresses a BMPR2 mutation found in a family with hereditary PAH (BMPR2+/R899X mice). The major focus based on exciting supporting data will be to define the potentially important but enigmatic role of fibroblasts as disease amplifiers in BMPR2+/R899X mice. This concept is driven in large measure by observations in patients and animal models of fibrosis localized around the vascular tree and that patients with fibrotic lung disease (such as idiopathic pulmonary fibrosis) also have significantly heightened likelihood of developing PAH. The fundamental question therefore is whether there is a causal relationship between aberrant BMPR2 signaling in pulmonary fibroblasts and the development and progression of PAH. In my first RO1 grant as an independent investigator I will test the hypothesis that BMPR2+/R899X fibroblasts become locked into a hyper-activated and pathogenic state that is crucial for the progression to fulminant disease. To test this hypothesis, I will identify the dysregulated signaling pathways that lead to aberrant fibroblast activation including how a reduction in BMPR2 levels leads to aberrant activation of Activin Receptor 2A (ACVR2A). Further, I will address how fibroblast activation in turn leads to vascular smooth muscle proliferation and thereby contributes to PAH. In response to the previous concerns we have thoroughly revised the proposal and provide new data showing feasibility and potential importance of the work. The intent ultimately will be that through the insights gained we can translate these findings into new therapies by defining previously unknown signaling pathways and anti-PAH drug targets.